In the body, whole blood viscosity increases as the blood flow through the capillaries decreases. Decreased blood flow can result from elevated levels of circulating blood cells, aggregation of blood cells, distortion of blood cell shape such as the sickling of red blood cells, elevated levels of circulating immunoglobulins, and gelation of certain types of immunoglobulins such as cryoglobulin. Numerous diseases are known to be associated with decreased blood flow leading to increased blood viscosity, and common symptoms include anemia, severe pain, and thrombotic complications.
Patients suffering from various plasma cell dyscrasias, for example, multiple myeloma, primary or Waldenstrom's macroglobulinemia, and certain heavy chain diseases which clinically mimic multiple myeloma routinely exhibit increased blood viscosity. These diseases are often associated with various dysproteinemias caused by overproduction of monoclonal immunoglobulins including markedly elevated plasma IgM concentrations and cryoglobulinemia. Systemic lupus erythematosus (lupus; SLE) and arthritis are also associated with similar dysproteinemias, and patients may exhibit increased whole blood viscosity.
Whole blood viscosity is often increased during complications in sickle cell disease. Under low oxygen tension, sickle cell deoxyhemoglobin (HbS) forms multi-stranded fibers (Rodgers, et al. 1987. Proc Natl Acad Sci USA 84:6157:6157-6161; Eaton, W. A. and Hofrichter, J. 1990. Adv Protein Chem 40:63-279) that force a red blood cell (RBC) into a crescent, or sickle, shape. Physiologically, decreased hemoglobin concentration associated with sickled RBCs impair blood flow, resulting increased whole blood viscosity.
Preventive treatment for these diseases is unknown, and therapy is symptomatic. Sickle cell and multiple myeloma patients are treated with hydration, analgesics for pain relief, and exchange transfusion for severe cases of anemia. Chemotherapy utilizing alkylating agents and corticosteroids is prescribed to multiple myeloma patients and macroglobulinernia patients. For hyperviscosity in macroglobulinemia patients, plasmapheresis is commonly practiced. Therapy for SLE and arthritis includes analgesics, arthralgias, and corticosteroids.
U.S. Pat. No. 5,654,334 discloses a method for decreasing pain comprising administering N-L-alpha-aspartyl-L-phenylalanine 1-methyl ester (APM) and certain derivatives having the following structure wherein R is H or an alkyl having 1-6 carbon atoms, as a pain reliever which is especially effective in relieving pain associated with osteoarthritis and multiple sclerosis. Further, International Application WO 97/00692 discloses a pharmaceutical preparation for administration to obtain an analgesic effect comprising APM derivatives wherein R is H or an alkyl containing 2 to 6 carbons as well as the antipyretic effect of APM and its derivatives. In a clinical trial, APM was demonstrated to alleviate the pain and inflammation of osteo- and mixed osteo- and rheumatoid arthritis by an unknown mechanism (Edmundson, A. B. and Manion, C. V. 1998. Clinical Pharmacology and Therapeutics 63:580-593).
International Application WO 00/18418 discloses a pharmaceutical preparation comprising APM or one of its derivatives wherein R is an alkyl useful in obtaining an antisickling effect in red blood cells. The application discloses that APM interacts with the HbS molecule to the extent that the stacking of the HbS molecules within the red blood cell is significantly altered, leading to a reduction in the capacity of red blood cells containing HbS to sickle with hypoxemia.
It has now been found that APM lowers whole blood viscosity in vivo, resulting in a viscosity modulating agent useful in the treatment of diseases of interest. A method of monitoring the progression of disease based on whole blood viscosity has also been found.